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WO2005059003A1 - Nouveaux polyesters - Google Patents

Nouveaux polyesters Download PDF

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Publication number
WO2005059003A1
WO2005059003A1 PCT/US2004/041942 US2004041942W WO2005059003A1 WO 2005059003 A1 WO2005059003 A1 WO 2005059003A1 US 2004041942 W US2004041942 W US 2004041942W WO 2005059003 A1 WO2005059003 A1 WO 2005059003A1
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WIPO (PCT)
Prior art keywords
polyester
poly
lactone
group
alkyl
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PCT/US2004/041942
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English (en)
Inventor
Venkatram P. Shastri
Xiao-Jun Xu
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The Children's Hospital Of Philadelphia
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Publication date
Application filed by The Children's Hospital Of Philadelphia filed Critical The Children's Hospital Of Philadelphia
Priority to US10/583,016 priority Critical patent/US20070117959A1/en
Publication of WO2005059003A1 publication Critical patent/WO2005059003A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/85—Germanium, tin, lead, arsenic, antimony, bismuth, titanium, zirconium, hafnium, vanadium, niobium, tantalum, or compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
    • C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
    • C08G63/08—Lactones or lactides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
    • C08G63/685—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen
    • C08G63/6852—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/91—Polymers modified by chemical after-treatment
    • C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids

Definitions

  • PHAs poly(alpha-hydroxy acids)
  • PLA poly(lactic acid)
  • PGA poly(glycolic acid)
  • PLGA poly(lactide-co-glycolide)
  • the invention provides a polyester comprising a macromeric unit, wherein the macromeric unit comprises (a) at least two lactone derived units, (b) an initiating core, and (c) a coupling unit.
  • the initiating core is linking at least two lactone derived units to form a macromerdiol.
  • the coupling unit is linking a plurality of macromerdiols.
  • the coupling unit and the initiating core have a carbon chain of a length sufficient to alter hydrophobicity of the polyester and thereby enable the polyester to degrade according to a surface erosion mechanism.
  • the polyester has the following structural formula: [-[A] m -[B]-[A] m -[D]-] x wherein A is a lactone derived unit, B is the initiating core, D is the coupling unit, m is a number of repeats from about 4 to about 60, and x is a number of macromeric units from 1 to about 100. In certain embodiments, m is 10 to 40.
  • B is represented by the formula: -[R,]- wherein Ri is a member selected from the group consisting of a C 2 -C ⁇ 4 linear alkyl, a substituted C 2 -C 14 alkyl having at least one substituent group, a C 2 -C
  • Ri is a member selected from the group consisting of Co, C 8 , Cio and C 12 alkyls, a poly(ether), poly(ethylenglycol), poly(amine), poly(propyleneoxide), block ABA copolymers of poly(oxyethylene) and poly(oxypropylene).
  • R 3 is a member selected from the group consisting of C 4 , C ⁇ , C 8 , and Cio alkyls.
  • a polyester comprising a macromeric unit, wherein the macromeric unit comprises (a) at least two lactone derived units, (b) an initiating core, wherein the diol derived unit is linking at least two lactone derived units to form a macromerdiol; and (c) a coupling unit, wherein the coupling unit is linking a plurality of macromerdiols and wherein the coupling unit and the diol derived unit have a carbon chain of a length sufficient to alter hydrophobicity of the polyester, and thereby enable the polyester to degrade according to a surface erosion mechanism.
  • the polyester of the invention comprising providing a lactone, providing a diol, providing a coupling agent, reacting the lactone with the diol in a presence of a catalyst to form a macromerdiol, and reacting the macromerdiol with the coupling agent to form the polyester.
  • the catalyst is a member selected from the group consisting of tin(II)-2-ethylhexanoate, aluminum isopropoxide, salts and oxides of yttrium and lanthanide.
  • the lactone is a member selected from the group consisting of lactones of alpha-hydroxy acids, lactones of beta-hydroxy acids, lactones of omega-hydroxy acids, lactones of gamma-hydroxy acids, lactones of delta-hydroxy acids, lactones of epsilon- hydroxy acids, p-dioxanone, cyclic carbonates, optical isomers thereof, substituents and mixtures thereof.
  • the lactone is lactide, ⁇ -caprolactone, propiolactone, butyrolactone, valero lactone, p-dioxanone, depsipeptide or a mixture thereof.
  • the diol has the following structural formula: HO-(R,)-OH wherein R] is a member selected from the group consisting of a C 2 -C 1 linear alkyl, a substituted C 2 -C 14 alkyl having at least one substituent group, a C 2 -C14 heteroalkyl, a C 2 -C ⁇ branched alkyl, an alkyl having at least one unsaturated bond, and a polymer.
  • the coupling agent is an acyl halide.
  • the coupling agent is a diacyl chloride derived from adipic acid, suberoic acid, sebacic acid, or dodecanoic acid.
  • a device manufactured from the polyester of the invention is adapted to be implanted in a body. In certain embodiments, at least a part of the device is adapted to deliver a bioagent.
  • the bioagent is an antibody, a viral vector, a growth factor, a bioactive polypeptide, a polynucleotide coding for the bioactive polypeptide, a cell regulatory small molecule, a peptide, a protein, an oligonucleotide, a gene therapy agent, a gene transfection vector, a receptor, a cell, a drug, a drug delivering agent, nitric oxide, an antimicrobial agent, an antibiotic, an antimitotic, an antisecretory agent, an anti-cancer chemotherapeutic agent, steroidal and non-steroidal anti-inflammatories, a hormone, an extracellular matrix, a free radical scavenger, an iron chelator, an antioxidant, an imaging agent, or a radiotherapeutic agent.
  • Fig. 1 is a reaction scheme depicting the preparation of polyesters of the invention, demonstrating (a) a reaction between a diol and a poly(hydroxy acid) (PHA)-derived lactone in the presence of a catalyst to form a mactomerdiol (MD) and (b) a reaction between the MD formed in the previous reaction and a coupling agent, an acyl halide, to form the polyester of the invention.
  • PHA poly(hydroxy acid)
  • Figs. 3A-3C are graphs demonstrating chemical characteristics of macromerdiol H20L, wherein Fig. 3 A is the FT1R spectrum, Fig. 3B is the ⁇ -NMR spectrum, and Fig. 3C is the ⁇ - 13C correlated (HSQC) spectrum.
  • Fig. 4A is the FTIR spectrum, and Fig. 4B is the ⁇ -NMR spectrum of polyester
  • FIG. 5 shows degradation profiles of polyesters of the invention (H20LC6, H40LC10, and 40LC10) as compared to profiles of PLA and P(dl)LGA (RG 503) at pH 10.
  • Fig. 6A-6C are graphs demonstrating chemical characteristics of macromerdiol diol D40L, wherein Fig. 6A is the FTIR spectrum, Fig. 6B is the 'HNMR spectrum, and Fig. 6C is the ⁇ - 13 C correlated (HSQC) spectrum.
  • Fig. 7 shows typical DSC curves of the macromer diol D40L and polyester D40LC10.
  • Figs. 8A-8C are graphs demonstrating chemical characteristics of polyester D40LC10, wherein Fig.
  • Fig. 8A is the FTIR spectrum
  • Fig. 8B is the 'HNMR spectrum
  • Fig. 8C is the ⁇ - l3 C correlated (HSQC) spectrum of the polyester.
  • Figs. 9A-9C are bar graphs showing the molecular weight polydispersity index (PDI) as a function of a type of the diacid dichloride (1: adipoyl chloride, 2: suberoyl chloride, 3: sebacoyl chloride, and 4: dodecanedioyl dichloride) and PLA/PLGA chain length for polyesters of the invention with the 1,6-hexanediol core (Fig. 9A), the 1,8-octanediol core (Fig.
  • PDI molecular weight polydispersity index
  • Figs. 10A- 10C are bar graphs showing the glass transition temperature (E g ) as a function of a type of the diacid dichloride (1 : adipoyl chloride, 2: suberoyl chloride, 3: sebacoyl chloride, and 4: dodecanedioyl dichloride) and PLA/PLGA chain length for polyesters of the invention with the 1,6-hexanediol core (Fig. 10A), the 1,8-octanediol core (Fig. 10B), or (c) the 1,12- dodecanediol core (Fig. 10C).
  • E g glass transition temperature
  • the polyester of the invention includes a macromeric unit, wherein the macromeric unit has (a) at least two lactone derived units, (b) an initiating core, and (c) a coupling unit, wherein the initiating core is linking at least two lactone derived units to form a macromerdiol, and wherein the polyester is capable of degrading according to the surface erosion mechanism.
  • the polyesters of the invention possess surface eroding characteristics being imparted by selecting the length and structure of the initiating core and the coupling unit.
  • the polyesters of the present invention are suitable for a wide range of biomedical applications including drug delivery, imaging, scaffolding for tissue engineering, coating of various surfaces such as, for example, implantable devices, and manufacturing of implantable devices, colloids and microparticles.
  • the primary driving force for the bulk erosion degradation mechanism in polymers such as poly(hydroxy acids) (PHAs) is the relative hydrophilicity of the polymer backbone. This allows for the penetration of the aqueous front beyond the surface of the polymer solid and into the bulk. Once degradation sets in, the accumulation of water-soluble degradation products within the polymer causes an osmotic in-flow of water that further accelerates the degradation process.
  • the response of the polymer at the water uptake phase must be influenced such that the progression of bulk erosion favoring events is arrested.
  • surface-eroding characteristics could be imparted to polymers such as PHAs, which ordinary degrade by the bulk erosion mechanism, by introducing moieties possessing long alkyl chains along the polymer chain.
  • the hydrophobicity (lipophilicity) of the polymer system can be modulated without significant changes to its crystallinity. The increase in lipophilicity would in turn diminish the water uptake and confer surface-eroding characteristics to the resulting polymer.
  • the present invention reduces or overcomes the above discussed deficiencies in polyesters by modifying the response to these polymers at the water uptake phase.
  • Synthesizing the polymers from at least one type of monomers possessing an alkyl chain backbone is believed to improve the hydrophobicity of the polymer system without detrimentally affecting its crystallinity. It is believed that this increased hydrophobicity in turn diminishes water uptake and confers surface eroding characteristics to the polymer.
  • Characteristics associated with the surface erosion mechanism include lower concentrations of degradation products around the implant and minimal changes in local pH.
  • Polymers possessing surface erosion characteristics are desirable because they can be used, for example, in drug delivery systems such as sustained release formulations of bioactive agents or in promoting bone growth around an implant.
  • POLYMER DESIGN AND SYNTHESIS Synthesis of a polyester of the present invention is carried out in two basic steps as show in Fig. 1.
  • First step involves a reaction between a lactone and a diol in a presence of a catalyst to produce macromerdiols (MDs).
  • MDs macromerdiols
  • Second step involves reacting MDs with a coupling agent to produce the polyester of the invention, wherein MDs are coupled together preferably as block polymers.
  • the lactone and the diol are provided at a molar ratio of about 5 to about 60.
  • the macrodiol and the coupling agent are provided at a molar ratio of about 1 to about 20.
  • Non-limiting examples of polyesters of the invention are polyesters derived from PHAs. Tables 2-4 represent polyesters of the invention derived from L-lactide and L-lactide/glycolide that exhibit surface-erosion-like behavior.
  • various MDs possessing varying degrees of hydrophilic-lipophilic balance were synthesized by initiating polymerization of L-lactide or a mixture of L-lactide and glycolide (3/1 molar ratio) to make polymers of various lengths using alkanediols of increasing C-chain lengths (as shown in Table 1).
  • the use of alkanediol initiators results in the formation of symmetrical MDs having alkane initiating cores and terminal hydroxyl groups.
  • the degree of polymerization (DP) of resulting polyesters depends on the molar ratio of the lactide/glycolide unit to alkanediol.
  • the MDs were coupled to each other using a coupling agent, for example, hydrophobic biocompatible acid halides of various C-chain lengths to further enhance hydrophobicity of the desired polyesters.
  • a coupling agent for example, hydrophobic biocompatible acid halides of various C-chain lengths to further enhance hydrophobicity of the desired polyesters.
  • polyesters of the invention are biocompatible as they are built from biocompatible moieties.
  • LACTONE A lactone used in the invention is a cyclic ester, which comprises at least one carboxy group and at least one oxy group.
  • Non-limiting examples of lactones which can yield polyesters of the invention include lactones of alpha-hydroxy acids such as lactide and glycolide, lactones of beta-hydroxy acids such as propiolactone, lactones of gamma-hydroxy acids such as butyurolactone, lactones of delta-hydroxy acids such as valerolactone, lactones of epsilon- hydroxy acids such as ⁇ -caprolactone, p-dioxanone, cyclic carbonates, optical isomers thereof (e.g., L-, DL- forms), substituents and mixtures thereof.
  • lactones of alpha-hydroxy acids such as lactide and glycolide
  • lactones of beta-hydroxy acids such as propiolactone
  • lactones of gamma-hydroxy acids such as butyurolactone
  • lactones of delta-hydroxy acids such as valerolactone
  • lactones of epsilon- hydroxy acids such as ⁇ -caprolactone
  • lactones used in the invention are capable of polymerizing respectively into, for example, poly(hydroxy acids) such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(caprolactone)(PCL), poly(lactide co-glycolide) (PLG), poly(gamma-hydroxy butyric acid) (pGHB) and poly(dioxanone).
  • poly(hydroxy acids) such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(caprolactone)(PCL), poly(lactide co-glycolide) (PLG), poly(gamma-hydroxy butyric acid) (pGHB) and poly(dioxanone).
  • lactones useful in the invention include lactone-lactams (cyclic amides) of alpha hydroxy acids and amino acids
  • R CH, or II
  • R ' A m ino
  • a cid n 1, 2 D epsipep tid es C yclic C arbonates such as, for example, depsipeptides.
  • the lactones used in the invention can be illustrated by the following structures: In a preferred embodiment, the lactone is a lactide. The reaction of the lactide with a diol is illustrated by Fig.1.
  • R 2 includes a C ⁇ -C 8 alkyl, wherein one or more carbons can be substituted with an aromatic group and/or a heteroatom such as, for example, N.
  • DIOL A diol used in the invention has the following structural formula: HO-(R,)-OH wherein Ri is a C 2 -C ⁇ 4 alkyl, including a linear alkyl, an alkyl having various substituent groups such as aromatic groups and halogen groups, an alkyl having heterogroups such as O, N, and S along the backbone, a branched alkyl, an alkyl having at least one unsaturated bond, and a polymer.
  • aromatic alkyls include phenyl and dimethylphenyl.
  • Preferred Ri includes C 6 , C 8 , C 10 and C, 2 alkyls, a polyether, poly(ethylenglycol) (PEG), poly(amine), poly(propyleneoxide), block ABA copolymers of poly(oxyethylene) (POE) and poly(oxypropylene) (POP, Pluronics).
  • PEG poly(ethylenglycol)
  • PEG poly(amine)
  • POP poly(oxypropylene)
  • Pluronics block ABA copolymers of poly(oxyethylene)
  • POP poly(oxypropylene)
  • Coupling agents are used in condensation polymerization reaction to link MDs to yield polyesters of the invention.
  • Non-limiting examples of such coupling agents are hydrophobic acyl halides, preferably diacid dichlorides.
  • diacyls are derived from adipic acid (C 6 ), suberoic acid (Cs), sebacic acid (Cio), and dodecanoic acid (C ⁇ 2 ).
  • the carbon chain length in acyl halides is one of the parameters that can be used to influence the hydrophobicity and degradation behavior of the polymer by altering the chain length until the desired effect of surface erosion characteristic in the polymer is reached.
  • POLYESTERS OF THE PRESENT INVENTION Polyesters of the present invention have the following structural formula: [-[A] m -[B]-[A] m -[D]-] x where m is a number of repeats from about 4 to about 60, and x is a number of macromeric units from about 1 to about 100.
  • the term "marcomeric unit” as used in this disclosure means a repeating unit formed from a combination of repeating lactone derived units (homo and hetero monomers), an initiating core, and a coupling unit.
  • lactone derived units constitute about 10% to about 99% of the polyester. In other embodiments, lactone derived units constitute 50% to 99% of the polyester. In certain embodiments, the lactone derived unit has a number average molecular weight of about 50 to about 12,000. In certain embodiments, the number average molecular weight is 50 to 6,000 or 50 to 2,000. In certain embodiments, the polyester has a molecular weight from about 20 KDa to about 120 KDa.
  • the polyesters of the present invention can be used in a wide range of biomedical applications including drug delivery, imaging, scaffolding for tissue engineering, coating of various surfaces such as, for example, implantable devices, manufacturing of implantable devices,colloids and microparticles (e.g., sized from about 10 nm to about lOOmicrons).
  • the polyester invention can be used in a vascular graft or orthopedic implant device such as a staple, a pin, a suture, a rod, a ligating clip, a vascular graft or a mesh.
  • the polyesters of the present invention can be used in, for example, bowel anastomosis, anastomosis of the ureter, sutureless anastomosis and nerve growth conduits. Additionally, it can be employed in fraction fixation devices such as, for example, a plate or screw.
  • the polyesters of the present invention can also be used for bone augmentation to heal defects in bone caused by trauma or tumor removal.
  • the polyesters of the present invention can also be used instead of a bone graft, thereby eliminating the need for extracting bone from another site of the patient. Another area of use for polyesters of the present invention is ligament reconstruction.
  • the orthopedic biomedical applications for the present invention can vary in hardness requirements.
  • the polyester of the present invention becomes softer; hence, one can tailor the chain length and resulting softness of the polyester product.
  • the total chain length of a diol, a repeating unit and a diacyl can also be tailored in accordance with desired applications.
  • the polyesters of the present invention can be used for manufacturing of e.g., biodegradable orthopedic or cardiovascular implants, they can also be used as drug delivery vehicles by incorporating various bioactive agents into the polyesters of the devices, wherein the release of the bioactive agents will be controlled by the surface erosion mechanism.
  • the polyesters of the present invention also can be used for drug delivery of a pharmaceutically active agent.
  • polyesters of the invention in drug delivery systems includes fabrication of reservoir caps in microchip delivery devices (see Grayson, A. C. R.; Choi, I. S.; Tyler, B. M.; Wang, P. P.; Brem, H; Cima, M. J.; Langer, R. Nature Materials 2003, 2, 767- 772).
  • Incorporation of bioactive agents into the polyesters of the invention can be performed by methods known in the art, wherein bioactive agents may be bound to the polyesters by covalent bonding or physically trapped within the polyester's structure. Covalent bonding can be achieved by various methods known in the art including chemical modification, photo- chemical activation, etc. For example, it would be useful to include an antibiotic in an implant.
  • polyesters of the invention in combination with bioactive agents include a wafer for oral administration or implant, a microsphere, microcapsule, or colloidal composition, wherein the bioactive agent is covalently or non-covalently associated with the polyester or entrapped in the polyester. Association of bioactive agents with polyester of the invention can be performed by methods known in the art as described above.
  • bioactive agents include an antibody, a viral vector, a growth factor, a bioactive polypeptide, a polynucleotide coding for the bioactive polypeptide, a cell regulatory small molecule, a peptide, a protein, an oligonucleotide, a gene therapy agent, a gene transfection vector, a receptor, a cell, a drug, a drug delivering agent, nitric oxide, an antimicrobial agent, an antibiotic, an antimitotic, dimethyl sulfoxide, an antisecretory agent, an anti-cancer chemotherapeutic agent, steroidal and non-steroidal anti-inflammatories, a hormone, an extracellular matrix, a free radical scavenger, an iron chelator, an antioxidant, an imaging agent, and a radiotherapeutic agent.
  • the biomaterial can be either component of an affinity-ligand pair.
  • affinity ligand pairs include avidin-biotin and IgG-protein A.
  • the biomaterial can be either component of a receptor-ligand pair.
  • One example is transferring and its receptor.
  • Other affinity ligand pairs include powerful hydrogen bonding or ionic bonding entities such as chemical complexes. Examples of the latter include metallo-amine complexes.
  • Nucleic acid decoys or synthetic analogues can also be used as pairing agents to bind a designed gene vector with attractive sites.
  • DNA binding proteins can also be considered as specific affinity agents; these include such entities as histones, transcription factors, and receptors such as the glucocorticoid receptor.
  • POLYMER CHEMICAL AND MECHANICAL CHARACTERIZATION Various conventional methodologies are available to assess chemical and mechanical characteristics of the polymers of the present invention.
  • Chemical characteristics for example, can be assessed with ⁇ and 13 C-NMR, which can be used to ensure purity of building blocks of the polymer and to characterize the final polymer composition with respect to group analysis, degree of polymerization, and monomer incorporation ratio.
  • FTIR can be used to verify monomer and polymer purity and to analyze degradation products.
  • Gel permeation chromatography is useful in determining the number and weight average molecular weight and polydispersity of the polymer against traditional standards such as polystyrene and PMMA.
  • the modulus ( ⁇ ) of fibers and films can be determined by using ASTM methods with an Instron testing equipment
  • the attachment and proliferation of NIH 3T3 fibroblasts can be used as a model system to measure the biocompatibility of the polymers of the present invention.
  • Cell proliferation can be determined by using an MTT assay.
  • Osteo-conductivity and compatibility of the polymers of the present invention can also be used in a standard animal model such as a trans-cortical rabbit tibia model. Osteo- conductivity and compatibility are preferably assessed after implantation in an appropriate animal model.
  • the osteo-conductivity of the polymer can be further enhanced with the addition of calcium salts such as hydroxyapatite (Hap), tricalcium phosphate (TCP) and beta-glycerol phosphate into the polymer implant.
  • calcium salts such as hydroxyapatite (Hap), tricalcium phosphate (TCP) and beta-glycerol phosphate into the polymer implant.
  • the remainder of the polymer material can be mechanically removed and further analyzed.
  • the polymer Prior to further analysis, the polymer can be treated to remove organic components with an enzyme solution such as trypsin and collagenase la, present in a Hank's balanced salt solution. Following the removal of organic components, the polymer can be dried under vacuum. NMR or SEM can then be used to evaluate the chemical characteristics of the removed sample.
  • the MDs (synthesized a described in Example 2) were linked using hydrophobic diacid dichlorides of varying carbon length (C ⁇ , C 8 , Cio, and C ⁇ ) to form higher molecular weight (MW) polyesters.
  • MW molecular weight
  • the synthesis of polyesters derived from MDs with adipoyl chloride is described below. 3 g of the MD was dissolved in 40 mL of MeCl in a 100-mL round-bottom flask. To this solution, 0.55 g of adipoyl chloride was added drop-wise at RT. After about lh, 0.61 g of triethylamine was added drop-wise to the flask, and the contents of the flask were stirred for an additional 4h at RT.
  • polyesters were obtained by condensation polymerization, by linking the MDs using a variety of hydrophobic diacid dichlorides as shown in Fig.1, step (b). Similarly to the MDs, corresponding polyesters were also readily soluble in THF even though the PLA content in the polyester ranged from about 80 to 96 wt%.
  • the molecular weight ( w ) of the polyesters ranged from about 20 KDa to 120 KDa /mol with polydispersity index (PDI) ranging from about 1.5 to 6. This corresponds to polyesters composed of 4 to 30 MD units since the molecular weight of MDs ranged from 1.4 (10 lactide or glycolide units) to 5.6 (40 lactide or glycolide units) KDa/mol.
  • the FTIR and ⁇ -NMR spectra are shown in Figs.4A - 4B.
  • the absence of the peak associated with the terminal hydroxy proton of the MD H20L, at 2.65 ppm and the appearance of peaks between 2.3 -2.6 ppm due to the -CH 2 protons of adipoyl chloride are indicative of polymer formation.
  • EXAMPLE 4 In Vitro Degradation of Polymer Wafers. Polymer wafers (7.8 mm diameter, 1 mm thickness, 50 mg/pellet) were prepared by compression of polymer powder in hardened stainless steel molds under a pressure of 32 MPa at
  • the wafers were submersed in phosphate buffer adjusted to pH 5, 7.4, and 10 and hydrated for a period of 15 days under constant stirring at 37 °C, with buffer solutions being replaced every 72 hours. Hydrated weights as well as pH of solutions were measured and recorded every 72 h during this period. On day 15th, wafers were removed and dried for 72 h in a vacuum oven at 40 °C. Dry mass was recorded and wafers were re-hydrated, with buffer solution, which was changed every 48 h. The drying procedure was repeated on days 20, 25, etc. of the study in order to obtain the dry mass of the wafers.
  • H20LC10 H20 sebacoyl chloride fiber-like solid 91 0 soluble 31140 6 0 31 33 101 08 115 49 123 27
  • O10LC8 O10L suberoyl chlo ⁇ de viscous soft solid 80 1 soluble 19256 5 6 -15 63 no no
  • O20LC6 O20L adipoyl chlo ⁇ de fiber-like solid 91 8 soluble 22891 2 0 38 69 104 64 1 17 44 124 86
  • O20LC8 O20L suberoyl chloride fiber-like solid 91 0 soluble 23385 3 0 28 75 92 66 1 10 79 122 67
  • O20LC10 O20L sebacoyl chlo ⁇ de fiber-like solid 90 2 soluble 34665 5 4 15 80 52 93 104 71 86 15 1 18 49
  • O30LC6 O30L adipoyl chlo ⁇ de fiber-like solid 94 5 soluble 129862 3 9 47 13 1 14 96 133 54 144 06
  • O30LC10 O30L sebacoyl chlo ⁇ de fiber-like solid 93 4 soluble 39584 4 2 28 63 46 09 1 15 50 76 32 138 77
  • O40LC6 O40L adipoyl chlo ⁇ de fiber-like solid 95 6 soluble 20290 2 5 44 22 103 43 135 27 144 54
  • O40LC8 O40L suberoyl chloride fiber-like solid 95 2 soluble 25622 2 6 42 42 88 12 126 82 145 06
  • O40LC10 O40L sebacoyl chlo ⁇ de fiber-like solid 94 7 soluble 40471 4 0 37 06 80 50 145 16 118 54
  • O40LC12 O40L dodecanedioyl fiber-like solid 94 3 soluble 39045 3 4 33 39 47 35 144 79 dichloride 75 04 116 14

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Polyesters Or Polycarbonates (AREA)

Abstract

L'invention concerne un polyester qui comprend un motif macromère, ce motif comportant (a) au moins deux motifs dérivés d'une lactone, (b) un noyau initiateur et (c) un motif de couplage. Le noyau initiateur relie les motifs dérivés d'une lactone de manière à former un diol macromérisé, le motif de couplage et le noyau initiateur comportant une chaîne carbonée d'une longueur suffisante pour modifier le caractère hydrophobe du polyester et permettre ainsi à ce dernier de se dégrader par érosion surperficielle. Les polyesters de l'invention peuvent être utilisés dans une large gamme d'applications biomédicales, y compris l'apport de médicaments, l'imagerie, les échafaudages en ingénierie tissulaire, le revêtement de diverses surfaces telles que, par exemple, des dispositifs implantables, ainsi que comme colloïdes et microparticules. Le schéma réactionnel de la figure 1 décrit la préparation des polyesters de l'invention.
PCT/US2004/041942 2003-12-15 2004-12-15 Nouveaux polyesters WO2005059003A1 (fr)

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US10/583,016 US20070117959A1 (en) 2003-12-15 2004-12-15 Novel polyesters

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US52971603P 2003-12-15 2003-12-15
US60/529,716 2003-12-15

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GB2433743A (en) * 2005-12-30 2007-07-04 Ind Tech Res Inst Aliphatic polyester copolymer
WO2007094940A2 (fr) * 2006-02-10 2007-08-23 Advanced Cardiovascular Systems, Inc. Appareil médical implantable avec revêtement en polyester d'administration de médicament par érosion de surface
WO2007131893A1 (fr) * 2006-05-15 2007-11-22 Gkss- Forschungszentrum Geesthacht Gmbh Copolymères multiblocs ayant des propriétés de mémoire de forme
EP2014695A1 (fr) * 2007-06-23 2009-01-14 Industrial Technology Research Institut Compositions de polymère en polyester aliphatique et son procédé de préparation
EP2144576A1 (fr) * 2007-04-24 2010-01-20 Tyco Healthcare Group LP Macromères biodégradables
EP2417987A3 (fr) * 2010-08-13 2015-07-01 Covidien LP Sutures à érosion de surface
WO2015161841A3 (fr) * 2014-04-23 2016-02-25 Martin-Luther-Universität Halle-Wittenberg Systèmes supports injectables et implantables, à base de polyesters modifiés d'acides dicarboxyliques avec des di- ou polyols, servant à la libération contrôlée de principes actifs

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US6565874B1 (en) * 1998-10-28 2003-05-20 Atrix Laboratories Polymeric delivery formulations of leuprolide with improved efficacy
US8470359B2 (en) 2000-11-13 2013-06-25 Qlt Usa, Inc. Sustained release polymer
US7846361B2 (en) 2006-07-20 2010-12-07 Orbusneich Medical, Inc. Bioabsorbable polymeric composition for a medical device
EP2073754A4 (fr) 2006-10-20 2012-09-26 Orbusneich Medical Inc Composition polymère bioabsorbable et fond de dispositif médical
US7959942B2 (en) 2006-10-20 2011-06-14 Orbusneich Medical, Inc. Bioabsorbable medical device with coating
WO2009052095A1 (fr) * 2007-10-17 2009-04-23 Advanced Liquid Logic, Inc. Stockage de réactif et reconstitution pour un dispositif de manipulation de gouttelettes
US9631244B2 (en) 2007-10-17 2017-04-25 Advanced Liquid Logic, Inc. Reagent storage on a droplet actuator
US20090281230A1 (en) * 2008-05-09 2009-11-12 Ashland Licensing And Intellectual Property Llc Branched low profile additives and methods of production
JP5694940B2 (ja) 2008-10-11 2015-04-01 ラトガース，ザ ステート ユニバーシティ オブ ニュー ジャージー 医療用途のための相分離した生体適合性ポリマー組成物
WO2011014859A1 (fr) 2009-07-31 2011-02-03 Rutgers, The State University Of New Jersey Polymères biocompatibles pour dispositifs médicaux
EP2486081B1 (fr) 2009-10-11 2018-12-05 Rutgers, The State University of New Jersey Polymères biocompatibles pour dispositifs médicaux
WO2013116804A2 (fr) 2012-02-03 2013-08-08 Rutgers, The State Of University Of New Jersey Biomatériaux polymères dérivés de monomères phénoliques et leurs utilisations à des fins médicales
US11472918B2 (en) 2012-02-03 2022-10-18 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
FI128487B (en) * 2013-05-06 2020-06-15 Teknologian Tutkimuskeskus Vtt Oy Glycolic acid polymers and process for their preparation
US10774030B2 (en) 2014-12-23 2020-09-15 Rutgers, The State University Of New Jersey Polymeric biomaterials derived from phenolic monomers and their medical uses
WO2016103224A2 (fr) 2014-12-23 2016-06-30 Rutgers, The State University Of New Jersey Monomères et polymères de diphénol iodés biocompatibles
CN109320701B (zh) * 2018-08-30 2020-11-10 深圳市聚亿新材料科技股份有限公司 一种基于改性聚乳酸的可降解果蔬抗菌保鲜袋的制备方法

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Cited By (13)

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US7902303B2 (en) 2005-12-30 2011-03-08 Industrial Technology Research Institute Aliphatic polyester polymer compositions and preparation method thereof
GB2433743B (en) * 2005-12-30 2009-10-14 Ind Tech Res Inst Aliphatic polyester polymer compositions and preparation method thereof
GB2433743A (en) * 2005-12-30 2007-07-04 Ind Tech Res Inst Aliphatic polyester copolymer
WO2007094940A2 (fr) * 2006-02-10 2007-08-23 Advanced Cardiovascular Systems, Inc. Appareil médical implantable avec revêtement en polyester d'administration de médicament par érosion de surface
WO2007094940A3 (fr) * 2006-02-10 2008-01-10 Advanced Cardiovascular System Appareil médical implantable avec revêtement en polyester d'administration de médicament par érosion de surface
US8021678B2 (en) 2006-02-10 2011-09-20 Advanced Cardiovascular Systems, Inc. Implantable medical device with polymer coating in a surface area to volume ratio providing surface erosion characteristics
WO2007131893A1 (fr) * 2006-05-15 2007-11-22 Gkss- Forschungszentrum Geesthacht Gmbh Copolymères multiblocs ayant des propriétés de mémoire de forme
EP2144576A1 (fr) * 2007-04-24 2010-01-20 Tyco Healthcare Group LP Macromères biodégradables
EP2144576A4 (fr) * 2007-04-24 2012-11-21 Tyco Healthcare Macromères biodégradables
US8748558B2 (en) 2007-04-24 2014-06-10 Covidien Lp Biodegradable macromers
EP2014695A1 (fr) * 2007-06-23 2009-01-14 Industrial Technology Research Institut Compositions de polymère en polyester aliphatique et son procédé de préparation
EP2417987A3 (fr) * 2010-08-13 2015-07-01 Covidien LP Sutures à érosion de surface
WO2015161841A3 (fr) * 2014-04-23 2016-02-25 Martin-Luther-Universität Halle-Wittenberg Systèmes supports injectables et implantables, à base de polyesters modifiés d'acides dicarboxyliques avec des di- ou polyols, servant à la libération contrôlée de principes actifs

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